Process of cyclizing alkylidene substituted aminomethylenemalonates

ABSTRACT

ALKYLIDENE AR-AMINOMETHYLENEMALONATES, WHERE AR IS AN AROMATIC RADICAL HAVING ONE OR TWO AROMATIC RINGS WHICH CAN BE BRNZENOID OR FIVE- OR SIX-MEMBERED HETEROAROMATIC, ARE PREPARED BY REACTING THE APPROPRIATE AROMATIC-AMINE WITH A MIXTURE OF A TRIALKYL ORTHOFORMATE OR TRIALKYL ORTHOACETATE AND AN ALKYLIDENE MALONATE. THE ALKYLIDENE AR-AMINOMETHYLENEMALONATES ARE THEN CYCLIZED BY HEATING TO PROVIDE AN IMPROVED PROCESS FOR PREPARING VARIOUS HETEROCYCLIC COMPOUND, E.G., A 4-HYDROXYQUINOLINE FROM AN ALKYLIDENE ANILIONOMETHYLENEMALONATE, A 4HPYRIDO(1,2-A)PYRIMIDIN-4-ONE FROM AN ALKYLIDENE 2-PYRIDYLAMINOMETHYLENEMALONATE, A 4H - PYRIMIDO(1,2 - A) PYRIMIDINE-4-ONE FROM AN ALKYLIDENE 2-PYRIMIDYLAMINOMETHYLENEMALONATE. THE CYCLIZED PRODUCTS ARE USEFUL AS INTERMEEIATES FOR THE PREPARATION OF ANTIMALARIALS AND ANTI-INFLAMMATORY AGENTS.

pnited States Patent Int. c1.co1d 33/18 US. Cl. 260-289 4 ClaimsABSTRACT OF THE DISCLOSURE Alkylidene Ar-aminomethylenemalonates, whereAr is an aromatic radical having one or two aromatic rings which can bebenzenoid or fiveor six-membered heteroaromatic, are prepared byreacting the appropriate ar'omatic-amine with a mixture of a trialkylorthoformate or trialkyl orthoacetate and an alkylidene malonate. Thealkylidene Ar-aminomethylenemalonates are then cyclized by heating toprovide an improved process for preparing various heterocycliccompounds, e.g., a 4-hydroxyquinoline from an alkylideneanilinomethylenemalonate, a 4H- pyrido[1,2-a1pyrimidin-4-one from analkylidene 2-pyridylaminomethylenemalonate, a 4H pyrimido[l,2-a]pyrimidine-4-one from an alkylidene 2-pyrimidylaminomethylenemalonate.The cyclized products are useful as intermediates for the preparation ofantimalarials and anti-inflammatory agents.

This invention relates to aromatic amine derivatives, to a process fortheir preparation, to processes utilizing said derivatives asintermediates, and to certain products produced by said processes.

This application is a division of my copending application Ser. No.735,566, filed June 10, 1968 and now US. Pat. 3,642,797, issued Feb. 15,1972, which in turn is a continuation-in-part of application Ser. No.640,359, filed May 22, 1967 and now abandoned, which in turn is acontinuation-in-part of application Ser. No. 464,850, filed June 17,1965 and now abandoned.

The invention sought to be patented, in one composition aspect, residesin the class of chemical compounds which I depict as having a molecularstructure of the Formula I where Ar is l-2 ringed aryl, R is hydrogen orloweralkyl, R and R are each lower-alkyl, and, R is hydrogen or methyl.

The term 1-2 ringed aryl, as used throughout this specification, e.g.,designated as Ar in Formula I, means aromatic radicals having one or twoaromatic rings which can be benzenoid or fiveor six-memberedheteroaromatic, among which are, for purposes of illustration butwithout limiting the generality of the foregoing, phen- 'ice yl,naphthyl, biphenylyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,thiazolyl, tetrazolyl, pyrazolyl, quinolyl and coumarinyl radicals.Preferred embodiments, because of their commercial practicability due toavailability of intermediates and because of their use in ahereinbelowdescribed new process to prepare 4-hydroxyquinolines, are thecompounds of Formula I where R is hydrogen and Ar is phenyl. Here andelsewhere throughout this specification, it will be understood that thebenzene ring of phenyl can bear any kind and number of substituents suchas would occur to the man skilled in organic chemistry, e.g., suchsubstituents, solely for illustration and without limiting thegenerality of the foregoing, including loweralkyl, lower-alkoxy,lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, halo,trihalomethyl, nitro, amino, lower-alkylamino, lower-alkanoylamino,benzyloxy, hydroxy, benzyl, and the like. When the benzene ring ofphenyl is substituted, there are preferably from one to threesubstituents which can be in any of the available positions of thebenzene ring, and where more than one substituent is present, they canbe the same or different and they can be in any of the various positioncombinations relative to each other. The term halo," as used here andthroughout the specification, includes chloro, bromo, iodo and fluoro.The terms lower-alkyl," lower-alkoxy, lower-alkylmercapto,lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylamino,loweralkanoylamino," and the like substituents, as used here andthroughout the specification, have preferably from one to six carbonatoms which can be arranged as straight or branched chains, and, withoutlimiting the generality of the foregoing, are illustrated by methyl,ethyl, n-propyl, isobutyl, n-hexyl, methoxy, isobutoxy, ethylmercapto,namylmercapto, ethylsulfinyl, isobutylsulfinyl, isopropylsulfonyl,n-butylsulfonyl, ethylamino, n-butylarnino, acetylamino andpropionylamino.

Other 1-2 ringed aryl radicals, e.g., naphthyl, biphenylyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, tetrazolyl, pyrazolyl,coumarinyl and quinolyl radicals, also can bear at available ring-carbonpositions substituents such as those illustrated above as substituentsof the benzene ring.

The term lower-alkyl as used throughout this specification, e.g., as themeaning for each of R and R in Formula I, means alkyl radicals havingfrom one to six carbon atoms inclusive, as illustrated by methyl, ethyl,n'propyl, isopropyl, 2-butyl, isobutyl, n-butyl, n-amyl, n-hexyl, andthe like. Preferred embodiments, because of their cost advantage, arethe compounds of Formula I where R and R are each methyl.

One process aspect of the invention resides in the preparation of thecompounds of Formula I by reacting the appropriate aromatic-amine of theformula Ar-NHR with a mixture of a trialkyl orthoformate or trialkylorthoacetate and an alkylidene malonate. This process is discussedhereinbelow and specifically illustrated as the first step of anotherprocess aspect of the invention, namely, the preparation of4-hydroxyquinolines utilizing the compounds of Formula I where R ishydrogen and Ar is phenyl, as defined above.

4-hydroxyquinolines are valuable intermediates. For

example, they have been converted to corresponding 4- haloquinolineswhich, in turn, have been reacted with certain alkylenediamines tosynthesize compounds having valuable chemotherapeutic properties, e.g.,reaction of 4,7-dichloroquinoline with S-diethylamino-Z-pentylamineyields 7-chloro-4-(5-diethylamino-2pentylamino)- quinoline, anantimalarial agent known as chloroquine.

Heretofore, the preferredmethod of preparing 4hydroxyquinolines has beenthe four-step Gould-Jacobs synthesis'illustrated as follows usinganiline (H) as an intermediate:

C(COOCzHs):

Thus, in step (1), aniline (II) is reacted with diethylethoxymethylenemalonate (III) to form diethyl anilinomethylenemalonate(IV), which is cyclized by heating in step (2) to form ethyl4-hydroxyquinoline-3-carboxylate (V). In step (3), the ester (V) ishydrolyzed to the acid (VI) which is then decarboxylated in step (4) toproduce 4-hydroxyquinoline (VII).

In contrast to the above four-step procedure, the process of myinvention resides in only two steps, which are illustrated below usinganiline (II) as an intermediate. As seen in the following illustration,no ester and no acid corresponding respectively to V and VI above areformed in my process.

5 COO R1 3 RaC (OR')a C II VIII IX where R is hydrogen or methyl, and R,R and R are each lower-alkyl. The aniline used in my process isunsubstituted in at least one of benzene ring positions ortho to theamino group. Optionally, the aniline canbe substituted by from one tofour of a variety of substituents at positions 2, 3, 4 or 5 of thebenzene ring thereby resulting in 4-hydroxyquinolines similarlysubstituted at positions 8, 7, 6 or 5, respectively; unsymmetricalanilines, e.g., those monosubstituted in the metaor 3-position andhaving no substituents at either the 2- or 6-position, yield a mixtureof isomeric 4-hydroxyquinolines (X), e.g., use of 3-chloroa ilineresults in a mix u e of fiydroxyquinoline and7-chloro-4-hydroxyquinoline which can be separated by known means.

In step (I) of my two-step process, an aniline (e.g., II) is reactedwith a mixture of a trialkyl orthoformate (VIII, R =H) or orthoacetate(VIII, R =CH and an alkylidene malonate (IX) to yield an alkylideneanilinomethylenemalonate (e.g., Ia) which, in step (2), is heated toform the 4-hydroxyquinoline (e.g., X) and a ketone, R COR and carbondioxide. Step (1) is preferably carried out by warming to about 50100C., with stirring, a mixture of the three reactants, preferred reactantsbeing triethyl orthoformate (VIII, R =H and R'=C H and isopropylidenemalonate (IX, R =R =CH The reaction also can be run by stirring thereactants at room temperature although the reaction may take longer or,also, it can be run at temperatures higher than 100 C., although to noparticular advantage. Many of the illustrative examples hereinbelow werecarried out in the presence of a small quantity of p-toluenesulfonicacid since it was first thought that the reaction was acid catalyzed,but it was later found out that the condensation could be effected inthe absence of an acid, in fact, even in the presence of excess sodiumacetate. Actually, the reaction is preferably run with no condensingagent. Yields are very good, ranging from about 70 to Step (2) of myprocess, i.e., the ring closure of the alkylideneanilinomethylenemalonate (e.g., Ia) to form the 4-hydroxy-quinoline(e.g., X), was carried out by heating the isopropyli deneanilinomethylenemalonate in an inert solvent at about 200 to 300 C.,preferably at about 225-275" C. Found particularly useful was arefluxing eutectic mixture of diphenyl and diphenyl ether (Dowtherm A).Other solvents that can be used are mineral oil, dibenzyl ether, diethyl'phthalate, nitrobenzene, and the like. Optionally, the reaction can berun by heating as above in the absence of a solvent. Yields of this stepusually range from about 50 to Alternatively, the above two steps of myprocess have been run consecutively without isolation of Compound Ia,the yields being comparable with those obtained by isolating saidintermediate.

Another variation of my process is the one-step reaction of thereactants of step (1) above using the reaction conditions of step (2) toform the 4-hydroxyquinolines.

This variation, which also afiords a way of preparing 4-hydroxyquinolines optionally bearing a 3-(lower-alkyl) substituent (R isillustrated as follows using aniline where R is hydrogen or methyl, R ishydrogen or loweralkyl, and R, R and R are each lower-alkyl. As above,the aniline used in the process is unsubstituted in at least one of thebenzene ring positions ortho to the amino group and, optionally, can besubstituted as noted hereinabove. In the above'one-step synthesis, amixture of an aniline (e.g., II) a trialkyl orthoformate (VIIIa, R =H)or orthoacetate (VIIIa, R =CH and an alkylidene(lower-alkyl) malonate(IXa) is heated as in step (2) above to form the 4-hydroxyquinoline(e.g., Xa) and a ketone, R COR and carbon dioxide.

In the above step (1) of my process, when another lower-aromatic amine(Ar-NH is substituted for an aniline, the corresponding alkylidene(lower aromatic) aminotutable ring-carbon atom ortho to its ring-carboncon-' nected to the nitrogen atom of the aminomethylenemalonate moiety,there is formed a (4-hydroxy-2-R -5,6- pyrido) -Ar compound; or, byheating a compound of Formula I where R is hydrogen, R and R are eachloweralkyl, R is hydrogen or methyl, and Ar is 1-2 ringed aryl which hasa ring-nitrogen atom adjacent to its ringcarbon connected to thenitrogen atom of the aminomethylenemalonate moiety, ring closure iseffected at the ringnitrogen atom to form a (4-oxo-6-R -2,3-pyrimido)-Arcompound. These ring closures thus are other process aspects of myinvention and, without limiting the generality of the foregoing, areillustrated as follows: heating an alkylidenenaphthylaminomethylenemalonate to form a 4-hydroxybenzoquinoline;heating an alkylidene 2-pyridylaminomethylenemalonate to form a4H-pyrido[l,2-a]pyrimidin-4-one; heating an alkylidene2-substituted-3-pyridylaminomethylenemalonate to form a4-hydroxy-8-substituted-1,7naphthyridine; heating an alkylidene2-unsubstituted-3-pyridylaminomethylenemalonate to form a4-hydroxy-1,5-naphthyridine; heating an alkylidene2-pyrimidylaminomethylenemalonate to form a 4H-pyrirnido[l,2-a]pyrimidin-4-one; heating an alkylidene5-uracilylaminomethylenemalonate to form a 1,5-dihydro-3H-pyrido[3,2-d]pyrimidine-2,4,8-trione; heating an alkylidene2-pyrazinylaminomethylenemalonate to form a 4H-pyrazino-[1,2-a1pyrimidin-4-one; heating an alkylidene 3-pyridazinylaminomethylenemalonate to form a 4H-pyrimido[1,2-b] pyridazin-4-one;heating an alkylidene Z-thiazolylaminomethylenemalonate to form apyrimido[2,1 b]thiazole; heating an alkylidene5-(lH-tetrazolyl)-aminomethylenemalonate to form a7-hydroxytetrazolo[1,5-a] pyrimidine; heating an alkylidene 2-phenyl (orlower-alkyl)-3-pyrazolylaminomethylenemalonate to form a l-phenyl(orlower-alkyl)-1H-pyrazolo[3,4b]pyridine; heating an alkylidene2-quinolylaminomethylenemalonate to form a 1H-pyrimido[1,2-a]quinolin-1-one; heating an alkylidene 3-quinolylaminomethylenemalonate to form a benzo [f]]1,7]naphthyridin'l-olg heating an alkylideneS-quinolylaminomethylenemalonate to form a 1,7-phenanthrolin 4 o1;heating an alkylidene 6-quinolylaminomethylenemalonate to form a4,7-phenanthrolin-1-ol; heating an alkylidene 7-quinolylaminomethylenemalonate to form a l,7-phenanthrolin--ol; heatingan alkylidene 8 quinolylaminomethylenemalonate to form al,10-phenanthrolin-4ol; and, heating an alkylidene6-coumarinylaminomethylenemalonate to form a10-hydroxy-3-oxo-3H-pyrano[3,2-f] quinoline.

The (4-hydroxy-2R -5,6-pyrido)-Ar and (4-oxo-6-R 2,3-pyrimido)-Arproducts of my process are useful, for example, the former are useful asintermediates in the preparation of antimalarial agents, as illustratedabove for the 4-hydroxyquinolines, and the latter haveanti-inflamrnatory activity, as illustrated below for the 4H- pyrido1,2-a1pyrimidi-n-4-ones.

It will be noticed that Ar in Formula I includes substituents which bytheir location may inhibit or even prevent the cyclization process toform the (4-hydroxy-2- R -5,6-pyrido) -Ar or (4-oxo-6-R -2,3-pyrimido)-Ar compound, e.g., the failure to cyclize isopropylidene2,6-dimethylanilinomethylenemalonate (by the blocking action of the 2-and 6-methyl substituents). Nevertheless, such compounds as these areuseful in establishing the limits of the cyclization reaction.

Also, it will be noticed that the compounds of Formula I Where R islower-alkyl do not undergo cyclization, e.g., the failure to cyclizeisopropylidene N-methylanilinomethylenemalonate (by the apparentblocking action of the N-methyl substituent). Such compounds are,nevertheless, useful in establishing the limits of the cyclizationreaction. Further, these N-(lower-alkyl) compounds have been tested bystandard pharmacological evaluation procedures and found to be useful inhaving biological activity, e.g., psychomotor depressant properties,barbiturate-potentiating activity, as illustrated further hereinbelow.

Another composition aspect of my invention sought to be patented isdescribed as residing in the class of chemical compounds which Idesignated 4H-pyridol[l,2-a] pyrimidin-4-ones of the Formula XI where Qrepresents from one to three substituents at positions 6, 7, =8 or 9 ofthe pyridopyrimidine nucleus selected from the group consisting oflower-alkyl, hydroxy, loweralkanoylamino, lower-alkylamino, benzyl,lower-alkoxy, lower-alkylmercapto, lower-alkylsulfinyl,lower-a-kylsulfonyl and trihalomethyl. These embodiments of my inventionare useful because of their anti-inflammatory properties as establishedby known pharmacological test procedures, e.g., inhibition ofcarrageenin induced local foot edema in fasted rats. For example, whentested by the above-noted procedure, these compounds when administeredorally at dose levels in the range of 25 to 200 mg./kg. were found toafford greater than 30% inhibition of edema, thereby evidencing theiranti-inflammatory activity. In contrast, the corresponding unsubstitutedcompound, i.e., Formula XI where Q is hydrogen, when tested by the sameprocedure, produced insignificant inhibition at 200 mg./kg.

The compounds of Formula XI were prepared by my above-described process,that is, by heating a Q-Z-pyridylaminomethylenemalonate (1b) to form aQ-4Hpyrido- [l,2-a]py'rimidin-4-one (XI), illustrated structurally asfollows:

0 I N L Q N b-o B1 A Q fi f 0-0 R: \N H l Ib XI The compounds of FormulaXI are useful both in free base form and in acid-addition salt form andboth forms are within the purview of the invention, and are consideredto be one and the same invention. The acid-addition salts are simply ausually more convenient form for use; and, in practice, use of the saltform inherently amounts to use of the base form. The acids which can beused to prepare the acid-addition salts are preferably those whichproduce, when combined with the free base, pharmacodynamicallyacceptable salts, that is, salts whose anions are relatively innocuousto the animal organism in pharmacodynamic doses of the salts, so thatthe beneficial properties inherent in the free base are not vitiated byside effects ascribable to the anions; in other words, the latter do notsubstantially affect the pharmacodynamic properties inherent in thecations. Appropriate pharmacodynamically acceptable salts within thescope of the invention are those derived from mineral acids such ashydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid,phosphoric acid, sulfamic acid, and sulfuric acid; and, organic acidssuch as acetic acid, citric acid,

tartaric acid, lactic acid, methanesulfonic acid, ethanesulfonic acid,quinic acid, and the like, giving the hydrochloride, hydrobromide,hydriodide, nitrate, phosphate, sulfamate, sulfate, acetate, citrate,tartrate, lactate, methanesulfonate, ethanesulfonate and quinate,respectively.

The acid-addition salts are prepared preferably by reacting the freebase and acid in an organic solvent, e.g., ethanol, in which case thesalt separates directly or can be obtained by concentration of thesolution.

Although pharmacodynamically acceptable salts are preferred, allacid-addition salts are within the scope of my invention. Allacid-addition salts are useful as sources of the free base form even ifthe particular salt per se is not desired as the final product, as forexample when the salt is formed for purposes of purification oridentification, or when it is used as an intermediate in preparing apharma'codynamically acceptable salt by ion exchange procedures.

Also encompassed by my invention are quaternary ammonium salts of theaforesaid 4H-pyrido[1,2-a]pyrimidin-4-ones of the Formula XI,quaternization occurring at the 1-ring nitrogen. These salts are alsouseful because of their anti-inflammatory properties and are useful forfurther identification of said 4H-pyrido[1,2-a]pyrimidin- 4-ones. Thequaternary ammonium salts are obtained by the addition of esters havinga molecular weight less than about 200 to the free base form of thecompounds. A preferred class of esters comprises lower-alkyl,loweralkenyl or benzyl esters of inorganic acids or organic sulfonicacids of the formula R -An where R is lower-alkyl, lower-alkenyl (having3 to 6 carbon atoms) or benzyl and An is an anion of a strong inorganicacid or an organic sulfonic acid, e.g., chloride, bromide, iodide,sulfate, methanesulfonate, benzenesulfonate, para-toluenesulfonate, andthe like. R when benzyl can bear any number and kind of inertsubstituents in the benzene ring, such substituents being illustratedby, but not limited to, lower-alkyl, lower-alkoxy, halo, nitro,lower-alkylamino, lower-alkylmercapto, and the like. R -An is thusillustrated by, but not limited to, methyl chloride, methyl bromide,methyl iodide, ethyl bromide, propyl chloride, isobutyl bromide, allylchloride, allyl bromide, methyl sulfate, methyl methanesulfonate, methylbenzenesulfonate, methyl p-toluenesulfonate, benzyl chloride, benzylbromide, p-chlorobenzyl chloride, p-nitrobenzyl chloride, o-chlorobenzylchloride, 3,4-dichlorobenzyl chloride, pmethoxybenzyl chloride, and thelike. The quaternary ammonium salts are prepared by mixing the free baseand the alkyl, alkenyl or benzyl esters in an organic solvent inertunder the conditions of reaction, for example, ethanol, methanol, ether,acetonitrile, dimethylformamide, dimethyl sulfoxide, and the like or,alternatively, in the absence of a solvent. Heating is preferably usedto facilitate the reaction, although quaternary formation takes place atroom temperature but a longer reaction time is needed. The quaternaryammonium salt separates directly or can be obtained by concentration ofthe solution.

Also encompassed by my invention are the l-oxide derivatives of thealkylidene pyridylaminomethylenemalonates of Formula Ib. Thesecompounds, which are prepared by the first step of my above-describedprocess by reacting a 2-aminopyridine-N-oxide with a tri-(lower-alkyl)orthoformate and an alkylidene malonate, are useful as characterizingderivatives of the compounds of Formula Ib.

Other aspects encompassed by my invention are: the bis-analogs of thecompounds of Formula I, i.e., the compounds of the Formula X11 Where Aris phenylene or as defined hereinbelow (i.e., Ar"-Z-Ar") and, R, R R andR are each defined as above for Formula I; the process of preparing thehis compounds of Formula XII which is carried out the same as thehereinabove-described process of preparing the compounds of Formula Ibut using an arylenediamine of the formula H NAr--NH and at least twomolar equivalents of the other reactants, i.e., a mixture of a trialkylorthoformate or trialklyl orthoacetate and an alkylidene malonate; and,the process of heating a com pound of Formula XII as describedhereinabove (for the process of heating a compound of Formula I) to formthe corresponding bis(4-hydroxy-2-R -5,6-pyrido) =Ar' compound when AIis phenylene which is unsubstituted at ring-carbon positions ortho toits ring-carbons connected to the nitrogen atoms of theaminomethylenemalonate moieties. Other bis-aspects of my invention arelike the above where -Ar'-- is replaced by where Ar" is phenylene and Zis a direct linkage, O, S, S-S, NH N(lower-alkyl), C(=O) orlower-alkylene. Here and elsewhere throughout this specification, itwill be understood that the benzene ring of phenylene, designated aboveas Ar and Ar", can bear any kind and number of substituents such aswould occur to theman skilled in organic chemistry, e.g., suchsubstituents being the same as those illustrated above for the benzenering of phenyl.

The molecular structures of the compounds of my invention areestablished by their mode of synthesis and corroborated by thecorrespondence of calculated and found values for the elementaryanalyses and by infrared (IR) spectral analyses.

The following examples will further illustrate the invention without,however, limiting it thereto.

EXAMPLE 1 (A) Isopropylidene 4 methoxyanilinomethylenemalonate.-Amixture containing 12.3 g. of 4-methoxyaniline, 14.8 g. of ethylorthoformate, 15.8 g. of isopropylidene malonate and 1.0 g. ofp-toluenesulfonic acid monohydrate was stirred at room temperature forone hour and then heated for ten minutes on a steam bath to boil oil theethanol formed by the reaction. The solid that remained wasrecrystallized from 500 cc. of ethanol usingdecolorizing charcoal toyield 15 g. (54%) of the product, isopropylidene4-methoxyanilinomethylenemalonate, M.P. 163-164.5 C. A 5.0 g. sample wasrecrystallized again from ethanol and dried in a vacuum oven at 60 C. toyield 4.2 g. of the white microcrystalline product, M.P. 163.2166.8 C.(corn).

Analysis.-Calcd. for C H NO (percent): C, 60.64; H, 5.45; N, 5.05. Found(percent): C, 60.84; H, 5.46; N, 4.97.

(B) 4-hydroxy-6-methoxyquinoline was prepared from isopropylidene 4methoxyanilinomethylenemalonate as follows: To ml. of Dowtherm A heatedto 245 C. was added, with stirring, 10.0 g. of isopropylidene4-methoxyanilinomethylenemalonate whereupon a vigorous reaction occurredand the acetone formed by the reaction was boiled from the reactionmixture. Heating was continued for an additional five minutes afterwhich time no more acetone boiled off. The reaction mixture was allowedto cool to room temperature with continued stirring and the solid thatseparated was collected, washed with n-pentane, air-dried andrecrystallized from Water to yield 2.9 g. of4-hydroxy-6-methoxy-quinoline, M.P. 245-247 C.

Analysis.Calcd. for C H NO (percent): C, 68.56; H, 5.18; N, 8.00. Found(percent): C, 68.86; H, 4.99; N, 8.01, 7.65.

The same product, 4-hydroxy-G-methoxyquinoline, is

obtained by heating isopropylidene 4-methoxyanilinomethylenemalonate at245 C. in the absence of a solvent.

9 EXAMPLE 2 (A) Isopropylidene 4methylanilinomethylenemalonate wasprepared following the procedure described in Example 1(A) using 10.7 g.of p-toluidine, 14.8 g. of ethyl orthoformate, 15.8 g. of isopropylidenemalonate and 1.0 g. of p-toluenesulfonic acid monohydrate. There wasthus obtained 17.5 g. (67%) of the product, isopropylidene4-methylanilinomethylenemalonate, M.P. 151-1525 C. Recrystallization ofa 5.0 g. sample from ethanol a second time yielded 4.7 g. of theproduct, M.P. 150.0- 151.2 C. (corn).

Analysis.-Calcd. for C H NO (percent): C, 64.36; H, 5.79; N, 5.36. Found(percent): C, 64.28; H, 6.06; N, 5.32.

(B) Following the procedure described in Example 1(B), isopropylidene4-methylanilinomethylenemalonate (12.5 g.) was heated in Dowtherm A (125ml.) to yield 4.1 g. of 4-hydroxy-6-methylquinoline. A samplerecrystallized from water and dried in a vacuum oven at 60 C. melted at237-239 C.

Analysis.-Calcd. for C H NO (percent): C, 75.45; H, 5.70; N, 8.80. Found(percent): C, 75.71; H, 5.59; N, 8.60, 8.70.

EXAMPLE 3 (A) Isopropylidene anilinomethylenemalonate was preparedfollowing the procedure described in Example 1(A) using 9.3 g. ofaniline, 14.8 g. of ethyl orthoformate, 15 .8 g. of isopropylidenemalonate and 1.0 g. of p toluenesulfonic acid monohydrate. There wasthus obtained 19.5 g. (79%) of the product, isopropylideneanilinomethylenemalonate, M.P. 154.0-l55.8 C. (corn).

Analysis.-Calcd. for C H NO (percent): C, 63.15; H, 5.30; N, 5.67. Found(percent): C, 63.44; H, 5.16; N, 5.35.

(B) Ring closure of isopropylidene anilinomethylenemalonate (2.5 g.) inDowtherm A (25 ml.) as in Example 1(B) yielded 1.0 g. (69%) of4-hydroxyquinoline, M.P. 192-198 C.

EXAMPLE 4 (A) Isopropylidene 4-nitroanilinomethylenemalonate wasprepared following the procedure described in Example 1(A) using 13.8 g.of p-nitroaniline, 14.8 g. of ethyl orthoformate, 15.8 g. ofisopropylidene malonate and 1.0 g. of p-toluenesulfonic acidmonohydrate. There was thus obtained 19.5 g. (67%) of isopropylidene4-nitroanilinomethylenemalonate after one recrystallization fromacetonitrile. A 4.0 g. sample was recrystallized a second time fromacetonitrile to yield 3.7 g. of the product, M.P. 215.02.16.0 C. (corr.)with decomposition.

Analysis.--Calcd. for C H N (percent): C, 53.43; H, 4.14; N, 9.59. Found(percent): C, 53.62; H, 4.07; N, 9.63.

(B) Refluxing 2.9 g. of isopropylidene 4-nitroanilinomethylenemalonatein 58 ml. of Dowtherm A as in Example 1(B) yielded 1.7 g. (90%) of4-hydroxy-6-nitroquinoline, M.P. 338-339 C., with decomposition.

(C) 4-hydroxy-6-nitroquinoline was also obtained by heating a smallsample of isopropylidene 4-nitroanilinomethylenemalonate in refluxingnitrobenzene for about four minutes, allowing the reaction mixture tocool to room temperature, and collecting the product by filtration.

EXAMPLE (A) Isopropylidene 4-chloroanilinomethylenemalonate was preparedfollowing the procedure described in Example 1(A) using 12.8 g. ofp-chloroaniline, 14.8 g. of ethyl orthoformate, 15.8 g. ofisopropylidene malonate and 1.0 g. of p-toluenesulfonic acidmonohydrate. After one recrystallization from ethanol, there wasobtained 23.5 g. (84%) of isopropylidene4-chloroanilinomethylenemalonate, M.P. 209.0209.4 C. (corn), withdecomposition.

Analysis.Calcd. for C H ClNO (percent): C,

10 55.43; H, 4.29; N, 4.98. Found (percent): C, 55.18; H, 4.07; N, 4.84.

(B) 6-chloro-4-hydroxyquinoline (0.8 g., 44%) was obtained following theprocedure described in Example 1(B) using 2.8 g. of isopropylidene4-chloroanilinomethylenemalonate and 30 ml. of Dowtherm A.

(C) 6chloro-4-hydroxyquinoline was prepared in one step using thereactants of 5 (A) as follows: A mixture containing 2.5 g. ofp-chloroaniline, 3.0 g. of ethyl orthoformate, 3.2 g. of isopropylidenemalonate and 56 ml. of Dowtherm A was slowly heated to C. with stirringover a period of thirty minutes. Heating of the resulting clear solutionwas then accelerated. At C., bubbles began to form. After ten minutesthe temperature was 251 C. Evolution of bubbles had been very rapidabove 200 C. but by 230 C., bubbling had subsided somewhat and thesolution began to turn red. The reaction mixture was allowed to cool toroom temperature while being stirred. The precipitate was collected,washed well with n-pentane and air-dried to yield 1.5 g. (42%) of6-chloro- 4-hydroxyquinoline, M.P. 25l261 C.

EXAMPLE 6 (A) Isopropylidene 2-methylanilinomethylenemalonate wasprepared following the procedure described in Example 1(A) using 10.7 g.of o-toluidine, 14.8 g. of ethyl orthoformate, 15.8 g. of isopropylidenemalonate and 1.0 g. of p-toluenesulfonic acid monohydrate. There wasthus obtained 19.9 g. (76%) of isopropylidene2-methylanilinomethylenemalonate. A second recrystallization of a 5.0 g.sample from ethanol yielded 4.2 g. of the product, M.P. 120.2-121.8 C.(corr.).

Analysis.-Calcd. for C H NO (percent): C, 64.36; H, 5.79; N, 5.36. Found(percent): C, 64.26; H, 5.65; N, 5.52.

(B) Refluxing 7.5 g. of isopropylidene 2-methylanilinomethylenemalonatein 75 ml. of Dowtherm A as in Example 1(B) yielded 3.3 g. (72%) of4-hydroxy-8-methylquinoline, M.P. 211-215 C.

(C) Refluxing 7.5 g. of isopropylidene Z-methylanilinomethylenemalonatein 37.5 ml. of nitrobenzene as in Example 4(C) yielded 2.5 g. (54%) of4-hydroxy-8-methylquinoline, M.P. 213.5-215" C. Recrystallization ofthis product from water using decolorizing charcoal yielded 1.9 gb ofthe 4-hydroxy-S-methylquinoline, M.P. 215- 216 Analysis.Calcd. for C HNO (percent): C, 75.45; H, 5.70; N, 8.80. 'Found (percent): C, 75.53; H,5.41; N, 8.79.

EXAMPLE 7 (A) Isopropylidene 2-methoxyanilinomethylenemalonate.A mixturecontaining 12.3 g. of o-anisidine, 14.8 g. of ethyl orthoformate, 15.8g. of isopropylidene malonate and 1.0 g. of p-toluenesulfonic acidmonohydrate was stirred at room temperature. The reaction mixture warmedspontaneously and after ten minutes crystallized. The crystallizedmaterial was collected, recrystallized from ethanol and air-dried toyield 23.1 g. (83%) of isopropylidene Z-methoxyanilinomethylenemalonate,M.P. 153- 155 C. Recrystallization of a 5.0 g. sample from ethanolyielded 4.8 g. of the product, M.P. 154.0155.8 C. (corr.).

Analysis.-Calcd. for C H NO (percent): C, 60.64; H, 5.45; N, 5.05. Found(percent): C, 60.94; H, 5.33; N, 5.33.

(B) Refluxing 5.5 g. of the above product, isopropylidene2-methoxyanilinomethylenemalonate, in 55 ml. of Dowtherm A following theprocedure described in Example 1(B) yielded 0.6 g. of4-hydroxy-8-methoxyquinoline, M.P. -186 C.

Analysis.-Calcd. for C H NO (percent): C, 68.56; H, 5.18; N, 8.00. Found(percent): C, 68.58; H, 5.06; N, 7.96.

1 1 EXAMPLE 8 (A) Isopropylidene 2-nitroanilinomethylenemalonate wasprepared following the procedure described in Exampe 1(A) using 13.8 g.of o-.nitroaniline, 14.8 g. of ethyl orthoformate, 15.8 g. ofisopropylidene malonate and 1.0 g. of p-toluenesulfonic acidmonohydrate. There was thus obtained, after recrystallization fromacetonitrile, 14.1 g. (48%) of isopropylidene2-nitroanilinomethylenemalonate, M.P. 175177 C. A small sample foranalysis was recrystallized a second time from acetonitrile, M.P.180-181 C. with decomposition.

Analysis.Calcd. for C H N O (percent): C, 53.43; H, 4.14; N, 9.59. Found(percent): C, 53.29; H, 4.80; N, 9.44.

(B) Isopropylidene 2-nitroanilinomethylenemalonate (5.0 g.) wasconverted to 4-hydroxy-8-nitroquinoline (0.9 g.), M.P. 207209 C. byrefluxing in nitrobenzene (50 ml.) following the procedure described inExample 4(C) and recrystallizing from water using decolorizing charcoal.

Analysis.Calcd. for C H N O (percent): C, 56.84; H, 3.18; N, 14.73.Found (percent): C, 57.10; H, 3.05; N, 14.23.

(C) 4-hydroxy-8-nitroquinoline (3.7 g.) was obtained Iby refluxingisopropylidene 2-nitroanilino-methylenemalonate (7.0 g.) in Dowtherm A(140 ml.) following the procedure described in Example 1(B).

EXAMPLE 9 (A) Isopropylidene 4-methoxy-2-nitroanilinomethylenemalonate.Amixture containing 33.6 g. of 4-methoxy-2- nitroaniline, 29.6 g. oftriethyl orthoformate, 31.7 g. of isopropylidene malonate and 150 ml. ofabsolute ethanol was heated with stirring on a steam bath for tenminutes. The reaction mixture was then heated in vacuo for an additionalfifteen minutes to remove the solvent and the ethanol formed by thereaction. The remaining solid was recrystallized from acetonitrile,using decolorizing charcoal, to yield 47.3 g. (73.5%) of isopropylidene4-methoxy-2- nitroanilinomethylenemalonate, M.P. 203.0203.6 C. (corr.),with decomposition.

Analysis.Calcd. for C H N O (percent): C, 52.17; H, 4.38; N, 8.69. Found(percent): C, 52.28; H, 4.55; N, 8.75.

(B) Following the procedure described in Example 1(B) and using 10 g. ofisopropylidene 4-rneth0xy-2-nitroanilinomethylenemalonate and 150 ml. ofDowtherm A, there was obtained 4.9 g. (72%) of 4-hydroxy-6-methoxy-8-nitroquinoline, M.P. 229-230 C. Recrystallization of this compoundfrom ethanol, using decolorizing charcoal, yielded 3.7 g. of the productmelting at 228.0228.6 C. (corr.).

Analysis.Calcd. for C H N O (percent): C, 54.55; H, 3.66; N, 12.72.Found (percent): C, 54.75; H, 3.81; N, 12.48.

EXAMPLE 10 (A) isopropylidene 3-nitroanilinomethylenemalonate wasprepared followingthe procedure described in Example 1(A) using 13.8 g.of 3-nitroaniline, 14.8 g. of ethyl orthoformate, 15.8 g. ofisopropylidene malonate, and 1.0 g. of p toluenesulfonic acidmonohydrate. There was thus obtained 22.8 g. (78%) of the product, M.P.198201 C. 'with decomposition after recrystallization from about 1 literof acetonitrile. Recrystallization of a 5.0 g. sample from acetonitrilegave 4.2 g. of the product, M.P. l97.0203.8 C. (corr.) withdecomposition.

Analysis.Calcd. for C H N O (percent): C, 53.43; H, 4.14; N, 9.59. Found(percent): C, 53.34; H, 4.40; N, 9.75.

(B) To 50 ml. of dibenzyl ether heated to 250 C. was added with rapidstirring 5.0 g. of isopropylidene 3-nitroanilinomethylenemalonate. Afterevolution of carbon dioxide subsided (about thirty seconds), the mixturewas allowed to cool to room temperature with rapid stirring. Theresulting precipitate was collected, washed well with dry ether anddried to yield 1.4 g. (43%) of product, M.P. 297299 C. withdecomposition. This product, a mixture of 4-hydroxyS-nitroquinoline and4-hydroxy-7- nitroquinoline, was subjected to a thin layerchromatography (TLC) analysis as follows: A sample was placed on asilica gel plate with dimethylformamide and eluted with chloroform:10%acetic acid:l0% methanol. After spraying the plate with fiuorscein dye,two fluores cent spots appeared in addition to the dimethylformamidespot. Amounts roughly estimated by size and density of the spots were3:1 with the larger spot running ahead (the large spot presumablyrepresents the 7-nitro isomer). The product was then recrystallized fromdimethylformamide using decolorizing charcoal to yield 0.3 g. of 4-hydroxy-7-nitroquinoline, M.P. 360 C. with decomposition.

Analysis.Calcd. for C H N O (percent): C, 56.84; H, 3.18; N, 14.74.Found (percent): C, 56.77; H, 3.47; N, 14.47.

The above dimethylformamide filtrate was diluted with several volumes ofdry ether and the solid that separated was collected, washed with etherand dried to yield 0.4 g. of 4-hydroxy 5 nitroquinoline, M.P. 350 C.with decomposition. A mixed melting point with the 7-nitro isomer wasdepressed 50.

Analysis.-Calcd. for C H N O (percent): C, 56.84; H, 3.18; N, 14.74.Found (percent): C, 56.61; H, 3.26; N, 14.58.

EXAMPLE 11 (A) Isopropylidene 3 chloroanilinomethylenemalonate.A mixturecontaining 12.8 g. of 3-chloroaniline, 15.8 g. of isopropylidenemalonate, 14.8 g. of ethyl orthoformate and 1.0 g. of p-toluenesulfonicacid monohydrate was heated slowly. After one hour, the temperature hadrisen to 80 C. and about 11.4 g. of ethanol had distilled off. Thereaction mixture was then heated for an additional thirty minuteswhereupon the temperature rose to about C. The resulting crystallineproduct was recrystallized from about 1000 ml. of absolute ethanol toyield 22.4 g. (80%) of isopropylidene 3-chloroanilinomethylenemalonate,M.P. 167.6169.0 C.

Analysis.Calcd. for C H ClNO (percent): N, 4.98; CI, 12.59. Found(percent): N, 4.81; Cl, 12.45.

(B) Conversion of isopropylidene 3-chloroanilinomethylenemalonate into amixture of 5-chloro 4 hydroxyquinoline and 7-chloro 4 hydroxyquinolineand subsequent conversion of these isomers to the corresponding 4,5 (and7) dichloroquinolines are given as follows: To 30 ml. of refluxingDowtherm A was added with stirring 2.8 g. of isopropylidene 3chloroanilinomethylenemalonate. After an initial vigorous reaction, themixture was refluxed for ten minutes and cooled to room temperaturewhile stirring. The solid that separated was collected to yield 1.6 g.(89%) of a mixture of 5 chloro 4 hydroxy quinoline and7-chloro-4-hydroxyquinoline.

A mixture of 1.0 g. of the above mixture of isomers, 1 ml. of phosphorusoxychloride and 5 ml. of ethylene dichloride was warmed on a steam bathfor about five minutes and then poured into ice water which containedammonium hydroxide. The mixture was stirred until the ice melted and aninsoluble solid was filtered ofi. The layers were separated and theethylene dichloride layer was dried over anhydrous potassium carbonateand evaporated to dryness. The solid residue was taken up in nhexane andfiltered. After no solid separated from the hexane solution, the hexanewas allowed to evaporate over a period of four days. There was thusobtained 0.5 g. (45%) of a mixture of approximately equal parts of 4,5dichloroquinoline and 4,7 dichloroquinoline, M.P. 6769 C., as shown byTLC using ether as the developing solvent and authentic samples of eachcompound as standards.

13 EXAMPLE 12 6-chloro 4 hydroxy 3 methylquinoline was prepared asfollows: A mixture containing 2.0 g. of 4-chloroaniline, 2.7 g. oftriethyl orthoformate, 2.5 g. of isopropylidene methylmalonate, and 30ml. of Dowtherm A was heated slowly with stirring up to reflux, refluxedfor three minutes and then allowed to cool. The product that separatedwas collected and recrystallized from isopropyl alcohol to yield6-chloro-4-hydroxy-3-methylquinoline, M.P. 329-331" C.

Analysis.-Calcd. for C H CINO (percent): Cl, 17.24; N, 6.81. Found(percent): Cl, 17.76; N, 7.03.

EXAMPLE 13 (A) Isopropylidene 3 methylanilinomethylenemalonate wasprepared following the procedure described in Example 1(A) using 10.7 g.of m-toluidine, 14.8 g. of ethyl orthoformate, 15.8 g. of isopropylidenemalonate and 1.0 g. of p-toluenesulfonic acid monohydrate. There wasthen obtained 19.6 g. (75%) of isopropylidene 3-methylanilinomethylenemalonate, M.P. 119.5121.0 C. Recrystallization ofa 5.0 g. sample from ethanol yielded 4.7 g. of the product, M.P.115.0116.6 C. (corr.).

Analysis.Calcd. for C H NO (percent): C, 64.36; H, 5.79; N, 5.36. Found(percent): C, 64.52; H, 5.80; N, 5.25.

(B) Heating a sample of isopropylidene 3 methylanilinomethylenemalonatein refluxing Dowtherm A following the procedure described in Example11(B) yields a mixture of 4 hydroxy 5 methylquinoline and 4-hydroxy-7-methylquinoline.

EXAMPLE 14 (A) 4 heptylidene 4 nitroanilinomethylenemalonate [also named5 (4 nitroanilinomethylene) 4,6 dioxo- 2,2 di n propyl 1,3 dioxan].-Amixture containing 2.8 g. of 4-nitroaniline, 3.2 g. of triethylorthoformate and 4.0 g. of 4-heptylidene malonate was stirred on a steambath. When a precipitate formed before all of the aniline had gone intosolution, 20 ml. of ethanol was added and stirring was continued on thesteam bath for ten minutes. The reaction mixture was allowed to cool andthe precipitate was collected, recrystallized once from acetonitrile andonce from isopropyl alcohol to yield 5.5 g. of 4 heptylidene 4nitroanilinomethylenemalonate, M.P. 171.6-172.6 C. (corr.).

Analysis.Calcd. for C H N O (percent): C, 58.61; H, 5.79; N, 8.04. Found(percent): C, 58.56; H, 5.57; N, 8.03.

(B) 4-hydroxy 6 nitroquinoline was prepared from the product of Example14(A) as follows: To 60 ml. of Dowtherm A heated to 240 C. was addedwith stirring 3.0 g. of 4-heptylidene 4-nitroanilinomethylenemalonate.The reaction mixture was heated to 240 C. and held there for about twominutes and was then allowed to cool to room temperature with stirring.The precipitate was collected, washed with n-pentane to yield 1.4 g.(85%) of 4hydroxy-6-nitroquinoline, M.P. 334335 C. with decomposition.

EXAMPLE 15 (A) 4-heptylidene 3-nitroanilinomethylenemalonate.- To astirred solution containing 5.6 g. of 3-nitroaniline and 8.0 g. of4-heptylidene malonate dissolved in 50 ml. of warm ethanol was added 6.4g. of triethyl orthoformate, and the resulting mixture was stirred atroom temperature for about thirty minutes and then cooled. Theprecipitate was collected, recrystallized from isopropyl alcohol andwashed with n-pentane to yield 12.2 g. (87%) of 4-heptylidene 3nitroanilinomethylenemalonate, M.P. 138.0- 139.0 C.

Analysis.-Calcd. for C H N O (percent): C, 58.61; H, 5.79; N, 8.04.Found (percent): C, 58.51; H, 5.60; N, 7.96.

(B) A mixture of 4-hydroxy-5-nitroquinoline and4hydroxy-7-nitroquinoline was prepared from the above product of Example15(A) as follows: To 60 ml. of Dowtherm A heated to 240 C. was addedwith stirring 3.0 g. of 4-heptylidene 3-nitroanilinomethylenemalonate,the reaction mixture heated to 245 C. and then allowed to cool to roomtemperature with stirring. The precipitate was collected, washed withn-pentane and air-dried to yield 1.5 g. (91%) of a mixture containing4-hydroxy-5-nitroquinoline and 4-hydroxy-7-nitroquinoline in the ratioof about one to two, as determined by the TLC procedure described abovein Example 10(B).

EXAMPLE 16 (A) 4 heptylidene 3 chloroanilinomethylenemalonate.To amixture containing 10.0 g. of 4-heptylidene malonate and 8.0 g. oftriethyl orthoformate was added 6.4 g. of 3-chloroaniline; 25 ml. ofethanol was added to the resulting mixture. The mixture was heated on asteam bath until dissolution resulted, then allowed to cool and stand atroom temperature for two hours. The resulting mixture was cooled in iceand the product that separated was collected, recrystallized fromisopropyl alcohol and washed with n-pentane to yield 14 g. (83%) of4-heptylidene 3 chloroanilinomethylenemalonate, M.P. 121.5- 123.0 C.(corr.).

Analysis.Calcd. for C17H20C1NO4 (percent): C, 60.44; H, 5.97; Cl, 10.5.Found (percent): C, 60.49; H, 6.24; Cl, 10.7.

(B) Heating a sample of 4-heptylidene 3-ch10roanilinomethylenemalonatein refluxing Dowtherm A following the procedure described in Example11(B) yields a mixture of 5-chloro-4-hydroxyquinoline and7-chloro-4-hydroxyquinoline.

EXAMPLE 17 6-chloro-4hydroxy-2-methylquinoline.-A mixture containing12.8 g. of 4-chloroaniline, 17.8 g. of ethyl orthoacetate and 14.4 g. ofisopropylidene malonate was heated with stirring on a steam bathovernight, the ethanol formed by the reaction distilling off. Thereaction mixture containing isopropylidene 4 chloroanilinomethylmalonate [Formula I where Ar is 4-chlorophenyl, R is H, and R =R =R=methyl] was allowed to cool and then dissolved in 250 ml. of DowthermA. The solution was refluxed for five minutes and then allowed to coolto room temperature with stirring. The precipitate that separated wascollected, washed with n-pentane and dried to yield 1.2 g. (62%) of6-chloro-4-hydroxy-2-methylquinoline. A small amount of the product wasrecrystallized from dimethylformamide using decolorizing charcoal toyield the purified product, a yellow solid, M.P. 320-321 C. withdecomposition.

Analysis.-Calcd. for C H ClNO (percent): Cl, 18.31; N, 7.23. Found(percent): Cl, 18.17; N, 7.57.

Alternatively, 6-chloro-4-hydroxy-2-methylquinoline is obtained bydirectly heating the same quantities of 4-chloroaniline, ethylorthoacetate and isopropylidene malonate in Dowtherm A as above,omitting the heating on the steam bath.

EXAMPLE 18 (A) Isopropylidene 3 fiuoroanilinomethylenemalonate.-Amixture containing 11.1 g. of 3-fluoroaniline, 14.8 g. of triethylorthoformate and 15.8 g. of isopropylidene malonate was stirred andwarmed on a steam bath for a few minutes whereupon a vigorous reactionensued. The mixture set up to a cream-colored cake which wasrecrystallized from about 700 ml. of absolute ethanol to yield 24.9 g.(94%) of the white solid product, isopropylidene 3fiuoroanilinomethylenemalonate, M.P. 159.0- 160.0 C. (corn), afterdrying in a vacuum oven at 60 C. overnight.

Analysis.-Calcd. for C H FN0 (percent): C, 58.87; H, 4.56; F, 7.16.Found (percent): C, 58.65; H, 4.54; F, 7.46.

(B) Heating a sample of isopropylidene 3-fluoroanilinomethylenemalonatein refluxing Dowtherm A following the procedure described in Exampe11(B) yields a mixture of S-fluoro-4-hydroxyquinoline and 7-fluoro 4hydroxyquinoline.

EXAMPLE 19 (A) Isopropylidene 3-trifluoromethylanilinomethylenemalonatewas prepared following the procedure described in Example 18(A) using16.1 g. of 3-trifluoromethylaniline, 14.8 g. of triethyl orthoformateand 15.8 g. of isopropylidene malonate. There was thus obtained 28.3 g.(90%) of isopropylidene 3-trifluoromethylanilinomethylenemalonate, M.P.155.2156.2 C. (corr.), after one recrystallization from about 500 ml. ofabsolute ethanol using decolorizing charcoal.

Anaylsis.Calcd. for C H F NO (percent): C, 53.34; H, 3.84; F, 18.09.Found (percent): C, 53.09; H, 3.92; F, 17.80.

(B) Heating a sample of isopropylidene3-trifluoromethylanilinomethylenemalonate in refluxing Dowtherm Afollowing the procedure described in Example 11(B) yields a mixture of4-hydroxy-S-trifluoromethylquinoline and4hydroxy-7-trifluorornethylquinoline.

EXAMPLE (A) Isopropylidene 1-naphthylaminomethylenemalonate.A mixturecontaining 14.3 g. of l-naphthylamine, 14.8 g. of ethyl orthoformate,15.8 g. of isopropylidene malonate and 1.0 g. of p-toluenesulfonic acidmonohydrate was stirred at room temperature for about seven minutes,next heated on a steam bath for about ten minutes to distill off theethanol formed by the reaction, and then cooled to room temperature withstirring. The solid that separated was collected and recrystallized from95% ethanol to yield 23.8 g. (80%) of isopropylidene 1-naphthylaminomethylenemalonate. A 5.0 g. sample was recrystallized twoadditional times from ethanol to yield 4.3 g. of the product melting at149.2l50.8 C. (corr.).

Analysis.Calcd. for C H NO (percent): N, 4.71. Found (percent): N, 4.66,4.71.

(B) 4-hydroxybenzo(h)quinoline was prepared by cyclizing the product ofExample 20 (A) as follows: To 190 ml. of Dowtherm A heated to reflux wasadded in 3 to 4 g. portions with stirring 18.8 g. of isopropylidenel-naphthylaminomethylenemalonate. After a vigorous reaction subsided,the reaction mixture was cooled to room temperature with stirring. Theresulting precipitate was collected, washed well with n-pentane andair-dried to yield 10.2 g. (83%) of 4-hydroxybenzo(h)quinolinemonohydrate. A small portion was recrystallized from ethanol to yieldthe purified product melting at 250-251 C.

Analysis.-Calcd. for C H NO (percent): C, 79.98; H, 4.65; N, 7.17. Found(percent): C, 73.29; H, 5.63; N, 6.52, 6.56; H O, 8.37. Found (DryBasis) (percent): C, 79.98; H, 5.12; N, 7.12, 7.16.

EXAMPLE 21 (A) Isopropylidene 4 sulfamylanilinomethylenemalonate.-To awarm mixture containing 17.2 g. of 4-aminobenzenesulfonamide, 15.8 g. ofisopropylidene malonate, and 14.8 g. of triethyl orthoformate was addedwith stirring 0.5 g. of p-toluenesulfonic acid monohydrate, 200 ml. ofisopropyl alcohol was added and the resulting mixture was heated withstirring on a steam bath for five minutes and then allowed to cool. Theprecipitate was collected and recrystallized fromacetonitriledimethylacetamide (4:1), washed with ethanol and dried in avacuum oven at 70 C. to yield 12.5 g. of isopropylidene4-sulfamylanilinomethylenemalonate, M.P. 247.2249.2 C. (corr.) withdecomposition.

Analysis.--Calcd. for C H N O S (percent): N, 8.60; S, 9.82. Found(percent): N, 8.68; S, 9.79.

(B) Heating a sample of isopropylidene4-sulfamylanilinomethylenemalonate in Dowtherm A following the proceduredescribed in Example 1(B) yields 4-hydroxy-6- sultamylquinoline.

EXAMPLE 22 (A) Isopropylidene 3,5 dinitroanilinomethylenemalonate.To astirred mixture containing 9.3 g. of 3,5-dinitroaniline, 8.1 g. ofisopropylidene malonate and 45 ml. of absolute ethanol was added 7.6 g.of triethyl orthoformate and the resulting mixture was heated on thesteam bath with stirring for about fifteen minutes, allowing the ethanolto evaporate. The resulting yellow solid was recrystallized twice fromacetonitrile and dried in a vacuum oven to yield 3.1 g. of pale yellowcrystalline product, isopropylidene 3,5 dinitroanilinomethylenemalonate,M.P. 213.0214.0 C. (corr.) with decomposition.

Analysis.Calcd. for C H N O (percent): C, 46.30; H, 3.29; N, 12.46.Found (percent): C, 46.49, 46.55; H, 3.75, 3.59; N, 12.34.

(B) 5,7-dinitro 4 hydroxyquinoline was prepared by cyclizing the productof Example 22(A) as follows: To 200 ml. of Dowtherm A heated to reflux(250 C.) was added with stirring 5 .0 g. of isopropylidene3,5-dinitroanilinomethylenemalonate over a period of thirty seconds. Thereaction mixture was refluxed for an additional thirty seconds and wasthen allowed to cool to room temperature with stirring. The product thatseparated was collected, washed well with ether, triturated twice withboiling ethanol and dried in a vacuum oven to yield 1.2 g. (35%) of5,7-dinitro-4-hydroxyquinoline, M.P. 360 C.

Analysis.Calcd. for C H N O (percent): C, 45.97; H, 2.14; N, 17.87.Found (percent): C, 46.16; H, 2.13; N, 17.24.

EXAMPLE 23 (A) 2,2 dithiodi(4-chloro-ortho-phenylene)di(iminomethylidyne)bis[isopropylidene malonate].To a stirred mixturecontaining 97.3 g. of 2-amino-4-chlorophenyl disulfide, 94.0 g. ofisopropylidene malonate and 600 ml. of absolute ethanol was added 92.0g. of triethyl orthoformate and the resulting mixture was heated on asteam bath with stirring. Within a few minutes the reaction mixturebecame a solid yellow cake which was heated for an additional fortyminutes. The solid was boiled with 3.5 liters of acetonitrile, theundissolved solid was filtered off, and the filtrate was chilled in acold room overnight. The undissolved solid was recrystallized from twoliters of acetonitrile using decolorizing charcoal and air-dried toyield 27.6 g. of the product, M.P. 212212.5 C. with decomposition. Theprecipitate which separated from the larger portion of acetonitrile wascollected and air-dried to yield 101.4 g. of the product, M.P. 21021l C.with decomposition. The two samples were then dried in a vacuum ovenwhereupon there was obtained 26.8 g. of the charcoaled sample, M.P.215.02l7.0 C. (corr.) with decomposition and 98.7 g. of the uncharcoaledsample, M.P. 123 C. with decomposition A portion of the charcoaledsample was analyzed as follows:

Analysis.Calcd. for C H Cl N O S (percent): Cl, 11.34; S, 10.25. Mol.wt., 625.5. Found (percent): Cl, 11.31; S, 10.38. Mol. wt., 640i5%.

(B) 6-chloro-4-hydroxy-8-quinolyl disulfide was prepared by cyclizingthe product of Example 23 (A) as follows: To 63 ml. of Dowtherm A heatedto reflux was added with stirring over a period of ninety seconds, 6.3g. of2,2'-dithiodi(4-chloro-ortho-phenylene)di-(irninomethylidyne)bis[isopropylidenemalonate]. The reaction mixture was heated with stirring for anadditional ninety seconds and then allowed to cool to room temperaturewith stirring. The solid that separated was collected to yield theproduct, 6-chloro-4-hydroxy-8-quinolyl disulfide.

The following compounds are obtained by following the two-step proceduredescribed in Examples 1(A) and 1(B), using in the f rst step (like 1(A))corresponding 1? molar equivalentquantities of the appropriate aniline,ethyl orthoformate and isopropylidene malonate (use of p-toluenesulfonicacid monohydrate optional) and heating in the second step (like l(B))the resulting isopropylidene anilinomethylenemalonate in refluxingDowtherm A to form the corresponding .4-hydroxyquinoline:

isopropylidene 4-biphenylaminomethylenemalonate (from 4-biphenylylamine)and 4-hydroxy-6- phenylquinoline; i

isopropylidene 4-n-butoxyanilinomethylenemalonate (from4-n-butoxyaniline) and 6-n-butoxy-4- hydroxyquinoline;

isopropylidene 4-ethylanilinomethylenemalonate (from 4-ethylaniline) and6-ethyl-4-hydroxyquinoline;

isopropylidene 2,4-dimethylanilinomethylenemalonate (from2,4-dimethylaniline) and 6,8-dimethyl-4- hydroxyquinoline;

isopropylidene 4-methy1mercaptoanilinomethylenemalonate (from4-methylmercaptoaniline) and 4-hydroxy-6-methylmercaptoquinoline;

isopropylidene 4-ethylsulfinylanilinomethylenemalonate (from4-ethylsulfinylaniline) and 6-ethylsulfinyl-4- hydroxyquinoline;

isopropylidene 4-n-butylsulfonylanilinomethylenemalonate (from4-n--butylsulfonylaniline) and 6-nbutylsulfonyl-4-hydroxyquinoline;

isopropylidene 4-iodoanilinomethylenemalonate (from 4-iodoaniline) and4-hydroxyfi-iodoquinoline;

isopropylidene 4-n-butylaminoanilinomethylenemalonate (from4-n-butylaminoaniline) and 6-n-butylamino- 4-hydroxyquin0line;

isopropylidene 2-acetylaminoanilinomethylenemalonate (fromZ-acetylaminoaniline) and 8-acetylamino-4- hydroxyquinoline;

isopropylidene 4 propionylaminoanilinomethylenemalonate (from4-propionylaminoaniline) and 4-hydroxy-6-propionylaminoquinoline;

isopropylidene 4-benzyloxyanilinomethylenemalonate (from4-benzyloxyaniline) and 6-benzyloxy-4- hydroxyquinoline;

isopropylidene 4-hydroxyanilinomethylenemalonate (from 4-hydroxyaniline)and 4,6-dihydroxyquinoline;

isopropylidene 2-benzylanilinomethylenernalonate (from 2-benzylaniline)and 8-benzyl-4-hydroxyquinoline;

isopropylidene 3 benzylanilinomethylenemalonate (from 3-benzylaniline)and a mixture of 5-benzyl-4-hydroxyquinoline and7-benzyl-4-hydroxyquinoline;

isopropylidene 4-aminoanilinomethylenemalonate (from 4-aminoam'line) and6-amino-4-hydroxyquinoline;

isopropylidene Z-aminoanilinomethylenemalonate (from Z-aminoaniline) and8-amino-4-hydroxyquinoline;

isopropylidene 4-(unsubstituted-phenoxy)anilinomethylenemalonate [from4-(unsubstituted-phenoxy)aniline] and4-hydroxy-6-(unsubstituted-phenoxy) quinoline;

isopropylidene 3- (unsubstituted-phenoxy) anilinomethylenemalonate [from3-(unsubstituted-phenoxy)anline] and a mixture of4-hydroxy-5-(unsubstituted-phenoxy)quinoline and4-hydroxy-7-(unsubstitutedphenoxy) quinoline;

isopropylidene 4-(unsubstituted-phenylmercapto)-anilinomethylenemalonate [from4-(unsubstitutedphenylmercapto)aniline] and4-hydroxy-6-(unsubstituted-phenylmercapto) quinoline;

isopropylidene 4-anilinoanilinomethylenemalonate (from 4-anilinoaniline)and 6-anilino-4hydroxyquinoline;

isopropylidene 3,S-xylidinomethylenemalonate, M.P.

170-172 C., (from 3,5-xylidine) and 5,7-dimethyl-4-hydroxyquinoline;

isopropylidene 2,5-xylidinomethylenemalonate, M.P.

162-l63 C., (from 2,5 xylidine) and 5,8-dimethyl-4-hydroxyquinoline;

isopropylidene 3,4-xylidinomethylenemalonate, M.P. -137? Ci, (from3,4-xylidine) and a mixture of 5,6-dimethyl-4-hydroxyquinoline and6,7-dimethyl-4-hydroxyquinoline;

isopropylidene 2,3-xylidinomethy1enemalonate, M.P.

138-139" C., (from 2,3-xy1idine) and 7,8-dimethyl-4-hydroxyquinolineisopropylidene 2,4-xylidinomethylenemalonate, M.P.

146-147 C., (from 2,4-xylidine) and 6,8-dimethyl-4-hydroxyquino1ine.

.The following compounds are obtained by following the two-stepprocedure described in Examples 23 (A) and 23(B), using in the firststep (like 23 (A)) corresponding molar equivalent quantities of theappropriate diamine, triethyl orthoformate and isopropylidene malonateand heating in the second step (like 23(B)) the resulting 2, 2disubstituted-di(iminomethylidyne)bis[isopropylidene malonate] inDowtherm A to form the corresponding cyclized product:

2,5-dimethyl-1,4-phenylene-2,2'-di(iminomethylidyne) bis[isopropylidenemalonate] (from 2,5-dimethyl- 1,4-pl1enylenediamine) and4,9-dihydroxy-5,l0- dimethylpyrido [2,3- g] quinoline;

2,5-dichloro-1,4-phenylene-2,2'-di(iminomethylidyne) bis[is0pr0pylidenemalonate] (from 2,5-dichloro- 1,4-phenylenediainine) and5,10-dichloro-4,9- dihydroxypyrido [2,3-g] quinoline;

4,4'-diphenylylene-2,2'-di iminomethylidyne) bis [isop ropylidenemalonate], M.P. 224-225 C. with decomposition (from4,4-biphenylylenediamine) and bis(4-hydroxy-6-quinolyl);

2,2'-methylene-di(para-phenylene) di(iminomethyl- Following theprocedure described in Example 23 (A) using a molar equivalent quantityof 2,6-diamino-pyridine in place of 2-amino-4-chloropheny1 disulfide,there was obtained diisopropylidene 2,6pyridinediyl-bis(aminomethylenemalonate), M.P. 261-262 C. withdecomposition.

Following the two-step procedure described in Exampes 20(A) and 20(B)using a molar equivalent quantity of the appropriate naphthylamine inplace of l-naphthylamine in the first step, the following compounds areprepared:

isopropylidene 4-ethoxy-I-naphthylaminomethylenemalonate (using4-ethoxy-1-naphthylamine) and 6-ethoxy-4-hydroxyb enzo( h) quinoline;

isopropylidene 3,4-dimethyl-l-naphthylaminomethylenemalonate (using3,4-dimethyl-l-naphthylamine) and 5,6-dimethyl-4-hydroxybenzo (h)quinoline;

isopropylidene 4-benzyl-l-naphthylaminomethylenemalonate (using4-benzy1-1-naphthylamine) and 6-benzyl-4-hydroxyb enzo (h) quinoline;

isopropylidene 2-naphthylaminomethylenemalonate using Z-naphthylamine)and 1-hydroxybenzo(f) quinoline; and,

isopropylidene 4-chloro-3-methoxy-2-naphthylaminomethylenemalonate(using 4-chloro-3-methoxy-2- naphthylamine) and 6-chlor0-1-hydroXy-5-methoxybenzo (f) quinoline.

In addition to having utility as intermediates, compounds of Formula Ialso have been found to have antiviral activity when tested by standardprocedures; for example, when administered orally or subcutaneously atrespective dose levels of up to 400 or 200 mg./kg./day to mice infectedwith vaccinia virus, they were found to increase survival time overuntreated controls and to cure up to about 80% of the mice tested.

The actual determination of the numerical biological data definitive fora particular compound is readily obtained by standard test procedures,referred to above, by technicians versed in pharmacological testprocedures, without any need for any extensive expen'mentation.

I claim:

1. The process which consists of heating in an inert solvent at aboutZOO-300 C. a compound of the formula H Rs g-O where R and R are eachlower-alkyl, R is hydrogen or methyl, and Ar is aryl selected from thegroup consisting of phenyl, naphthyl, phenyl having from one to twosubstituents selected from lower-alkyl, lower-'alkoxy and halo,

phenyl having a single substituent selected from trihalomethyl,lower-alkylamino, lower-alkanoylamino, nitro, hydroxy, phenoxy andanilino, and naphthyl having a single substituent selected from halo andlo'wer-alkoxy, said aryl having a substitutable ring-carbon atom orthoto its ring-carbon connected to the nitrogen atom of theaminomethylenemalonate moiety, to form (4-hydroxy-2- R -5,6-pyrido)-Ar,where lower-alkyl in each instance is non-tertiary and has from one tosiX carbon atoms.

2. The process according to claim 1 which consists of heatingisopropylidene anilinomethylenemalonate to form 4-hydroxyquinoline whereanilino is unsubstituted or substituted as indicated in claim 1 forphenyl.

3. The process according to claim 1 which consists of heatingisopropylidene naphthylaminomethylenemalonate to formbenzo-4-hydroxyquinoline where naphthyl is unsubstituted or substitutedas indicated in claim 1 for naphthyl.

4. The process according to claim 3 which consists of heatingisopropylidene anilinomethylenemalonate to form 4-hydroxyquinoline.

References Cited UNITED STATES PATENTS 3,178,348 4/1965 Bickerson260-289 3,563,981 2/ 1971 Lesher 260-283 SY 2,504,896 4/ 1950 Snyder260-289 R 2,614,121 10/1952 Price 260-287 R 3,313,818 4/1967 Lesher260-289 R DONALD G. DAUS, Primary Examiner US. Cl. X.R.

260-283 SY, 287 R, 288 R Paton; No. 5,798 227 Dated March 19, 19715Inventor) George Y. Lesher It is certified Lhat error appears in the.above-identified patent and that said Letters Patent. are herebycorrected as shot-x1 below:

Column 1, line 6 1, "loweralkyl" should read lower-alkyl a Column 3,lines 17-23, the formula designated as V should read as follows:

\ COOC2H5 Column 5, line 16, "benzo[fjjl,7 should read benzo ['fj [1,7]

Column 6, line 12, "designated" should read designate Column 6, line 50,"carrageenin induced" should read carrageenin-induced Signed and sealedthis l8th.day of March 1975.

(SEAL) Attest a C. MARSHALL. DANN RU'I'F C. MASON Commissioner ofPatents and Trademarks Attesting Officer

